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Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen

Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen
Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen
The adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or 310 helices. A virtual screen was conducted for putative binders of the Grb2 SH3C domain. Of the top hits, 34 were validated experimentally by surface plasmon resonance spectroscopy and isothermal titration calorimetry. A subset of these molecules was found to inhibit the Grb2–Gab2 interaction in a competition assay, with moderate to low affinities (5: IC50 320 ?M). The most promising binders were based on a dihydro-s-triazine scaffold, and are the first small molecules reported to target the Grb2 SH3C protein-interaction surface.
0968-0896
4027-4033
Simister, Philip C.
d987348f-b37b-43e0-ada4-2af88478b350
Luccarelli, James
9afdfaf8-5c48-4110-a281-2eeeabb6c2ff
Thompson, Sam
99b7e34e-fe24-401c-b7b0-64e56cbbbcb1
Appella, Daniel H.
bee670ec-943d-4c29-9298-6e913792e20b
Feller, Stephan M.
e7db67f4-4579-4e4b-9c34-4ae440b4df6f
Hamilton, Andrew D.
048a6c75-91bf-4555-ab12-ce885eee65dd
Simister, Philip C.
d987348f-b37b-43e0-ada4-2af88478b350
Luccarelli, James
9afdfaf8-5c48-4110-a281-2eeeabb6c2ff
Thompson, Sam
99b7e34e-fe24-401c-b7b0-64e56cbbbcb1
Appella, Daniel H.
bee670ec-943d-4c29-9298-6e913792e20b
Feller, Stephan M.
e7db67f4-4579-4e4b-9c34-4ae440b4df6f
Hamilton, Andrew D.
048a6c75-91bf-4555-ab12-ce885eee65dd

Simister, Philip C., Luccarelli, James, Thompson, Sam, Appella, Daniel H., Feller, Stephan M. and Hamilton, Andrew D. (2013) Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen. Bioorganic & Medicinal Chemistry, 21 (14), 4027-4033. (doi:10.1016/j.bmc.2012.10.023).

Record type: Article

Abstract

The adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or 310 helices. A virtual screen was conducted for putative binders of the Grb2 SH3C domain. Of the top hits, 34 were validated experimentally by surface plasmon resonance spectroscopy and isothermal titration calorimetry. A subset of these molecules was found to inhibit the Grb2–Gab2 interaction in a competition assay, with moderate to low affinities (5: IC50 320 ?M). The most promising binders were based on a dihydro-s-triazine scaffold, and are the first small molecules reported to target the Grb2 SH3C protein-interaction surface.

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e-pub ahead of print date: 27 October 2012
Published date: 15 July 2013
Organisations: Chemistry

Identifiers

Local EPrints ID: 403608
URI: http://eprints.soton.ac.uk/id/eprint/403608
ISSN: 0968-0896
PURE UUID: c79bdd37-f719-451f-90e3-fc2054cbdd8b
ORCID for Sam Thompson: ORCID iD orcid.org/0000-0001-6267-5693

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Date deposited: 07 Dec 2016 13:28
Last modified: 20 Jul 2019 00:32

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Contributors

Author: Philip C. Simister
Author: James Luccarelli
Author: Sam Thompson ORCID iD
Author: Daniel H. Appella
Author: Stephan M. Feller
Author: Andrew D. Hamilton

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